Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)
| Autor: | Gino Cingolani, Maria Grazia Perrone, Antonio Scilimati, Paola Vitale, Roger S. Armen, Giuseppe Di Mauro, Savina Ferorelli, William L. Smith, Cosimo G. Fortuna, Andrea Panella |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Stereochemistry Crystal structure Selective inhibition 01 natural sciences Article Structure-Activity Relationship 03 medical and health sciences Mofezolac Oxidoreductase Drug Discovery medicine Humans Structure–activity relationship Molecule Cyclooxygenase Inhibitors Pharmacology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry Active site Isoxazoles General Medicine 0104 chemical sciences 030104 developmental biology Cyclooxygenase 1 biology.protein Cyclooxygenase medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 138:661-668 |
| ISSN: | 0223-5234 |
| Popis: | The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs. |
| Databáze: | OpenAIRE |
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